Solvent-free, microwave-assisted N-arylation of indolines by using low palladium catalyst loadings

Article abstract of DOI:10.1002/cssc.201100098

Indoline-based compounds are abundant in nature, and the indoline skeleton is an often-encountered scaffold in a range of biologically active alkaloids, pharmaceutically active compounds, and functional molecules (e.g., sensitizers for solar cells). The wide range of uses warrants further interest in the structural modification of this class of compounds. A series of substituted N-aryl indolines is prepared by a solvent-free, palladium-catalyzed procedure. The procedure requires only low loadings of catalyst, uses microwave irradiation, and starts from commercially available substrates. The method proceeds in good yields and in short reaction times with aryl bromides, chlorides, and iodides, also on 2-substituted indolines. The combination of solvent-free methods with microwave heating will further increase in importance in the search for more environmentally acceptable synthesis methods. Copyright

Full text of DOI:10.1002/cssc.201100098

DOI: 10.1002/cssc.201100098
Solvent-Free, Microwave-Assisted N-Arylation of Indolines
by using Low Palladium Catalyst Loadings
Luca Basolo,[a] Alice Bernasconi,[a] Elena Borsini,[a] Gianluigi Broggini,[b] and Egle M. Beccalli*[a]
Indoline-based compounds are abundant in nature, and the in-
doline skeleton is an often-encountered scaffold in a range of
biologically active alkaloids, pharmaceutically active com-
pounds, and functional molecules (e.g., sensitizers for solar
cells). The wide range of uses warrants further interest in the
structural modification of this class of compounds. A series of
substituted N-aryl indolines is prepared by a solvent-free, palla-
dium-catalyzed procedure. The procedure requires only low
loadings of catalyst, uses microwave irradiation, and starts
from commercially available substrates. The method proceeds
in good yields and in short reaction times with aryl bromides,
chlorides, and iodides, also on 2-substituted indolines. The
combination of solvent-free methods with microwave heating
will further increase in importance in the search for more envi-
ronmentally acceptable synthesis methods.
Introduction
Indoline-based compounds are abundant in nature, and the in-
doline skeleton is an often-encountered scaffold in a range of
biologically active alkaloids[1–3] and pharmaceutically active
compounds.[4,5] For example, Figure 1 shows the biologically
active alkaloid vindoline (1), as well as the angiotensin-convert-
ing enzyme inhibitor pentopril (2),[4a] substituted indolines with
cyclooxygenase-inhibitory activity (3),[4d] and indoline-5-sulfo-
namide compounds substituted on the indoline nitrogen atom
with aromatic or heterocyclic moieties (4), which are excep-
tionally potent and selective human b3 adrenergic receptor ag-
onists.[4c] Very recent patents report that N-heterocyclic indo-
line derivatives (5) are amyloid beta modulators.[4f] In addition,
N-arylindolines 6 have been successfully employed as chiral
auxiliaries in asymmetric synthesis[6] and in the field of ad-
vanced materials for hydrogen storage in fuels.[7] Highly effi-
cient organic sensitizers for dye-sensitizer solar cells have been
reported based on substituted N-arylindolines such as 7
(Figure 2).[8] This wide variety of uses warrants further interest
in the structural modification of this class of compounds.
Figure 2. Indolines as chiral auxiliaries (6) and sensitizers in solar cells (7).
Different types of procedures for the synthesis of indolines
can be found in literature.[9] Among these, inter- and intramo-
lecular transition-metal-catalyzed amination and carboamina-
tion reactions play an important role.[10] Nucleophilic aromatic
substitution has been reported as a key step to obtain the
functionalized indolines, most importantly N-arylated deriva-
tives, but the use of strong basic reagents and harsh reaction
conditions has limited the compatibility of this step with a
broad range of functional groups.[11]
Palladium-catalyzed reactions could be a preferred method
of functionalizing indoline derivatives through the formation
of a CÀN bond. For the generation of different arylamines, the
amination reaction has the broadest scope of all existing syn-
thetic methods in this field. The versatility and reliability of
[a] Dr. L. Basolo, A. Bernasconi, Dr. E. Borsini, Prof. Dr. E. M. Beccalli
DISMAB, Sezione di Chimica Organica “A. Marchesini”
Universitꢀ degli Studi di Milano
via Venezian 21,20133 Milano (Italy)
Fax: +39-02-50314476
E-mail: egle.beccalli@unimi.it
[b] Prof. Dr. G. Broggini
Dipartimento di Scienze Chimiche e Ambientali
Universitꢀ dell’Insubria
Figure 1. Biologically active indoline-containing compounds.
via Valleggio 11, 22100 Como (Italy)
ChemSusChem 2011, 4, 1637 – 1642
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1637

E. M. Beccalli et al.
these chemical transformations
is evident from the number of
academic and industrial groups
that use them. Owing to the im-
portance of arylamine deriva-
tives, there is not only an aca-
demic but also a strong com-
mercial interest in the amination
reaction, a fact that was pointed
out by an earlier publication by
Schlummer and Scholz.[12] As re-
ported, several CÀN couplings
have already been run at a pro-
duction scale of several hundred
kilograms, although in the litera-
Table 1. Optimization of reaction conditions.[a]
Entry
Catalyst[b]
Amount
[mol%]
Ligand[b]
Amount
[mol%]
Base
Equiv
T [8C]
t [h]
Yield [%]
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
2
2
2
2
2
5
1
5
1
1
1
0.5
BINAP
DPPF
DavePhos
IAPU
XantPhos
BINAP
BINAP
BINAP
IAPU
2
2
4
Cs2CO3
tBuOK
tBuOK
Cs2CO3
Cs2CO3
tBuOK
tBuOK
Cs2CO3
tBuOK
Cs2CO3
K2CO3
5
120
120
120
120
100
120
120
100
100
100
100
100
24
24
24
24
24
24
24
24
24
24
24
24
11
7
5
1.4
1.4
5
1.5
1.4
1.4
2
1.4
1.5
5
4
32
12
58
40
68
74
56
72
75
10
10
2
10
4
4
4
2
9
ture
a
somewhat
smaller
10
11
12
IAPU
IAPU
IAPU
number of processes has ap-
peared.[13]
K2CO3
5
As a part of our ongoing ef-
forts to develop synthetic appli-
cations of palladium-catalyzed
amination reactions for hetero-
cyclic substrates,[14] we began to
investigate the N-arylation reac-
[a] Reactions performed on 1 mmol of substrate. [b] BINAP=2,2’-bis(diphenylphosphino)-1,1’-binaphthalene,
DPPF=Bis(diphenylphosphino)ferrocene, DavePhos=2-dicyclohexylphosphino-2’-(N,N-dimethylamino)biphenyl,
IAPU=2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo [3.3.3]undecane, XantPhos=4,5-bis(diphenylphosphi-
no)-9,9-dimethylxanthene
tions of indolines following established conditions reported
earlier.[14b,c] A major drawback of the classical procedure is that
it requires catalyst loadings of 5–10 mol %, although a recent
work on aryl amination reported more environmentally benign
conditions and a catalyst loading of 0.5 mol%.[15]
prompted us to improve the reaction conditions by screening
different catalysts, ligands, and bases to achieve a maximum
yield of product. Besides the use of Pd2(dba)3 as catalyst, the
choice of ligand had a marked effect on the product yields (en-
tries 5 and 6), as did the choice of base (entries 9–11). In the
case of comparable results obtained with different bases (en-
tries 9 and 11), the use of cheaper K2CO3 is preferred. The best
result was obtained by using Pd2(dba)3 as catalyst, 2,8,9-triiso-
butyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (IAPU)
as ligand, K2CO3 as base, and toluene as solvent at 1008C for
24 h (entry 11). The use and efficiency of the ligand IAPU, offer-
ing steric bulk, in amination reactions is well-documented.[19]
Interestingly, lowering the amount of catalyst did not impact
the yield of coupling product (entry 12).
Herein, we describe a new protocol for amination reactions
of aryl halides with indolines. The protocol uses low catalyst
loadings, in the absence of solvent and under microwave heat-
ing. Avoiding the use of solvents is a crucial point for sustaina-
bility in organic synthesis[16] because it circumvents the need
for their supply, purification, and disposal. Particularly the latter
has been an important incentive for the development of sever-
al other solvent-free synthetic reaction protocols.[17] Although
solvent-free reactions often use classical laboratory equipment,
there is added value in the use of microwave heating. Gron-
now and co-workers reported that the use of microwave irradi-
ation can be expected to considerably reduce (by a factor of
up to 85) the amount of energy required to perform a reac-
tion, compared to conventional heating.[18]
After optimizing the reaction conditions, we explored the
feasibility of a greener alternative by attempting the reaction
without solvent under microwave irradiation.[20] Although sol-
vent-free reactions are often carried out by using one of the
reagents as solvent—deeply limiting the scope of the proce-
dure—our protocol is a real solvent-free procedure that sup-
ports the reagents on finely powdered K2CO3. Microwave-acti-
vation allowed the formation of N-aryl indolines in excellent
yields within a short reaction time (Table 2, entries 1 and 2).
Further lowering of the catalyst loading, to below 0.5 mol %,
had little influence on the product yield (entries 3–5).
The combination of solvent-free reaction conditions and mi-
crowave irradiation led to significantly reduced reaction times,
enhanced conversions, and offered several advantages for the
coupling reaction. That these more effective conditions could
be achieved for this reaction is important to its industrial appli-
cations and for the development of sustainable chemistry.
Having established optimized reaction conditions, some fea-
tures should be pointed out: (i) choosing Pd2(dba)3 as catalyst
proved essential; (ii) the use of commercial K2CO3 proved es-
sential, also. The latter aspect deserves some additional com-
ments: In particular, the K2CO3 must be finely powdered, be-
cause the total exposed area is increased markedly when the
particle size is reduced. In fact, when carrying out the reaction
on granular K2CO3 the yield dropped to one-third the yield
Results and Discussion
Initially, we explored the formation of N-arylindoline by using
indoline 8a and 2-bromopyridine 9a as model substrates
(Table 1). A preliminary, poor result obtained with Pd(OAc)2,
BINAP, Cs2CO3, and toluene as solvent at reflux for 24 h
(Table 1, entry 1; isolated yield of N-2-pyridylindoline: 11%)
1638
www.chemsuschem.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2011, 4, 1637 – 1642

Solvent-Free, Microwave-Assisted N-Arylation of Indolines
Table 2. Optimization of the solvent-free procedure.[a]
Table 4. N-arylation of indolines with aryl chlorides and iodides.[a]
Substrate
Product
Yield D
[%]
Yield MW
[%]
Entry
Pd2(dba)3
[mol%]
IAPU
[mol%]
Yield [%]
X
A
R’
11a
11b
11c
11d
11e
11g
11i
Cl
Cl
Cl
Cl
Cl
Cl
Cl
N
N
H
10aa
10ab
10ac
10ad
10ae
10ag
10ai
46
70
40
37
59
72
75
66
80
60
50
67
68
48
1
2
3
4
5
1
4
2
0.8
0.4
0.2
75
73
67
61
58
m-CH3
p-CN
0.5
0.2
0.1
0.05
CH
CH
CH
CH
CH
p-COOMe
p-NO2
p-OCH3
p-NO2
o-CH(OCH2)2
H
[a] Reactions performed on 1 mmol of substrate.
12f
12g
I
I
CH
CH
10af
10ag
68
88
71
84
p-OCH3
[a] Reactions performed on 1 mmol of substrate.
achieved when using powdered K2CO3. Likewise, the K2CO3
must be adequately hydrated, because the protocol does not
work if it is absolutely dry, and the yield is halved when it is
too hydrated. Finally, the K2CO3 powder must be packed well
after it is introduced into the reactor.
strates 9c–e), an electron-donating substituent (substrate 9g),
and different substituted indolines (substrates 8b–d) This pro-
cedure was not limited to aryl bromides, as aryl chlorides and
iodides also proved suitable partners and afforded similar re-
sults (Table 4). The data in Tables 3 and 4 also allow to com-
pare yields between traditional thermal heating with solvent
and microwave irradiation without solvent.
Oxidation byproducts, as substituted indoles, are normally
formed when carrying out the reaction by thermal heating.[21]
The use of microwave irradiation avoided the formation of
these oxidized byproducts, Ullmann-type biaryl byproducts,
and also minimized the formation of dehalogenated sub-
strates. While most coupling reactions described in literature
are conducted under inert conditions (i.e., exclusion of oxygen
and moisture by employing an inert-atmosphere glove-box),
the stability and the versatility of our catalytic system allowed
the reactions to be run under conditions less strict.
Finally, considering the synthetic importance of chiral indo-
lines, enantiopure 2-substituted indolines were obtained when
the reaction was performed on chiral substrates (Table 3,
entry 11). In fact, despite the presence of a base the (S)-indo-
line-2-carboxylic acid gave (S)-1-(4-nitrophenyl) indoline with
enantiomeric purity better than 99.5 %, as confirmed by chiral
HPLC analysis with an AD chiral column and in comparison
with a sample of the corre-
The reaction was extended to different aryl bromides
(Table 3), showing tolerance for electron-withdrawing (sub-
sponding racemic mixture syn-
thesized starting from (Æ)-indo-
Table 3. N-arylation of indolines with aryl bromides with conventional (D) and microwave (MW) heating.[a]
line-2-carboxylic acid. This result
is a rare example in which a
base-sensitive substrate is em-
ployed for a palladium-catalyzed
amination reaction.[22]
Indoline
8
Aryl bromide
Product
10
Yield D
[%]
Yield MW
[%]
R
9
A
R’
Conclusions
8a
8a
8a
8a
8a
8a
8a
8a
H
H
H
H
H
H
H
H
9a
9b
9c
9d
9e
9f
N
N
H
10aa
10ab
10ac
10ad
10ae
10af
78
0
57
30
5
52
68
70
76
24
71
62
75
59
77
45
m-CH3
p-CN
p-COOMe
p-NO2
H
p-OCH3
p-F
o-CH(OCH2)2
m-CH3
p-NO2
H
The described solvent-free, pal-
CH
CH
CH
CH
CH
CH
ladium-catalyzed
procedure,
using microwave irradiation,
proceeds smoothly and affords
good yields with low catalyst
loadings. A range of substituted
N-aryl indolines can be generat-
ed from commercially available
starting materials in short reac-
tion times, providing a cost-ef-
fective, mild, and environmen-
tally benign preparation proce-
9g
9h
10ag
10ah
8b
8b
8b
8c
CH3
CH3
CH3
COOH
COOCH3
9b
9e
9f
9e
9e
N
10bb
10be
10bf
10ce
10de
0
5
68
0
31
65
68
53
54
CH
CH
CH
CH
p-NO2
p-NO2
8d
51
[a] Reactions performed on 1 mmol of substrate.
ChemSusChem 2011, 4, 1637 – 1642
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemsuschem.org
1639

E. M. Beccalli et al.
1-(4-Cyanophenyl)-indoline 10ac:[25] Elemental analysis: calcd (%)
for C15H12N2 (220.1): C 81.79, H 5.49, N 12.72; found: C 81.50, H
5.96, N 12.35.
dure. We believe that the combination of solvent-free methods
with microwave heating will further increase in importance in
the search for green laboratory-scale synthesis methods.
1-(4-Carbomethoxyphenyl)-indoline 10ad: Light-yellow solid, m.p.
1
98–1008C, H NMR (200 MHz, CDCl3, 208C, TMS): d=7.98—8.05 (m,
Experimental Section
2H), 7.10–7.31 (m, 5H), 6.85 (ddd, J=0.9, 7.5, 8.2 Hz, 1H), 4.00 (t,
J=8.4 Hz, 2H), 3.91 (s, 3H), 3.15 ppm(t, J=8.4 Hz, 2H). 13C NMR
(50 MHz, CDCl3, 208C, TMS): d=167.1 (s), 148.1 (s), 145.6 (s), 132.1
(s), 131.3 (s), 127.4 (d), 125.5 (d, 2C), 121.4 (s), 120.6 (d), 115.6 (d,
2C), 109.9 (d), 52.0 (t), 51.9 (q), 28.3 ppm(t). IR (KBr): n˜ =1670 cmÀ1
MS (ESI) m/z(%): 254.1 (100) [M+H]. Elemental analysis: calcd (%)
for C16H15NO2 (253.1): C 75.87, H 5.97, N 5.53; found: C 75.61, H
6.10, N 5.50.
Melting points were determined on a Bꢁchi B-540 heating appara-
tus and are uncorrected. 1H NMR and 13C NMR spectra were ob-
tained on a VARIAN 200 instrument. Chemical shifts are given in
ppm downfield from SiMe4. 13C NMR spectra are H-decoupled and
1
multiplicities were determined by the APT pulse sequence.
Typical reaction procedures for the synthesis of N-aryl indo-
lines
1-(4-Nitrophenyl)-indoline 10ae:[26] Orange solid, m.p.130–1318C,
1H NMR (200 MHz, CDCl3, 208C, TMS): d=8.18–8.26 (m, 2H), 7.15–
7.36 (m, 5H), 6.83 (ddd, J=0.9, 7.3, 8.4 Hz, 1H), 4.07 (t, J=8.3 Hz,
2H), 3.21 ppm(t, J=8.3 Hz, 2H). 13C NMR (50 MHz, CDCl3): d=149.4
(s), 144.5 (s), 139.9 (s), 132.7 (s), 127.5 (d), 125.9 (d, 2C), 125.8 (d),
121.9 (d), 115.0 (d, 2C), 110.8 (d), 52.3 (t), 28.2 (t). MS (ESI) m/z(%):
241.3 (100) [M+H]. Elemental analysis: calcd (%) for C14H12N2O2
(240.3): C 69.99, H 5.03, N 11.66; found: C 69.89, H 5.09, N 11.62.
Procedure 1 (solvent, thermal heating): K2CO3 (5 mmol, 691 mg)
was suspended in toluene (10 mL) in an oven-dried round bottom
flask, the suspension was flushed with nitrogen for 10 min, then
aryl halide (1 mmol), Pd2(dba)3 (0,01 mmol, 10 mg), IAPU
(0,04 mmol, 14 mg), and indoline (1 mmol) were added (in this
exact order). After 5 min of further nitrogen flushing the reaction
mixture was refluxed for 24 h. After this time the suspension was
cooled to room temperature, ethyl acetate (10 mL) was added, and
the mixture was filtered over Celite. The resulting solution was
washed three times with brine, dried with sodium sulphate, fil-
tered, and the solvent evaporated under reduced pressure. The
residue was purified by flash column chromatography using
hexane/ethyl acetate (4:1) as eluent. The solid compounds were
crystallized with hexane/diethyl ether.
1-Phenylindoline 10af:[21a] Elemental analysis: calcd (%) for C14H13N
(195.26): C 86.12, H 6.71, N 7.17; found: C 85.98, H 6.55, N 7.02.
1-(4-Methoxyphenyl)indoline 10ag:[25b] Elemental analysis: calcd
(%) for C15H15NO (225.3): C 79.97, H 6.71, N 6.22; found: C 80.02, H
6.91, N 6.02.
1-(2-(1,3-Dioxolan-2-yl)-4-fluorophenyl)indoline
10ah:
Purple-
1
brown oil. H NMR (200 MHz, CDCl3, 208C, TMS): d=7.25–7.40 (m,
2H), 6.96–7.18 (m, 3H), 6.72 (ddd, J=0.9, 7.3, 8.2 Hz, 1H), 6.28 (1H,
d, J=7.3 Hz, 1H), 6.08 (d, J=1.6 Hz, 1H), 3.64–4.20 (m br, 6H),
3.14 ppm(t, J=8.2 Hz, 2H). 13C NMR (50 MHz, CDCl3, 208C, TMS):
d=161.1 (d, J=246 Hz), 151.9 (s), 141.3 (dd, J=3.0 Hz), 138.7 (d,
J=8.0 Hz), 130.4 (s), 127.6 (dd, J=8.1 Hz), 127.5 (d), 124.8 (d), 118.8
(d), 118.0 (dd, J=23.8 Hz), 114.4 (dd, J=23.8 Hz), 108.9 (d), 99.65
(d, J=1.3 Hz), 65.7 (t, 2C), 57.4 (t), 29.2 ppm(t). MS (ESI) m/z(%):
286.1 (100) [M+H]. Elemental analysis: calcd (%) for C17H16FNO2
(285.3): C 71.56, H 5.65, N 4.91; found: C 71.52, H 5.70, N 4.83.
Procedure 2 (solvent-free, microwave heating): A round-bottom
flask was charged with Pd2(dba)3 (0,005 mmol, 5 mg) and the aryl
halide (1 mmol). Then 4 g of finely powdered K2CO3 was added. At
this point the IAPU (0,02 mmol, 7 mg) was added on the resulting
surface of K2CO3 and a solution of indoline (1 mmol) in 10 mL
CH2Cl2 was used to dissolve the reactant and suspend K2CO3. The
CH2Cl2 was then removed under reduced pressure and recovered.
The residual powder was diluted with 1 g of K2CO3 and grinded
with mortar and pestle for 5 min. A microwave oven reactor was
charged with the reactant powder, which was compacted as much
as possible. After microwave heating at 1408C for 20 min at a
350 W, a flash silica gel column was charged with the powder and
eluted with hexane/ethyl acetate (4:1) to recover purified product.
A hexane/diethyl ether recrystallization was performed, where pos-
sible, to improve purity.
Note: the only exception for procedure 2 was the case of indoline-
2-carboxylic acid, which needed an additional work-up step before
column chromatography and special attention for the column
itself: after microwave heating, the powder was dissolved in water
and extracted with Et2O to remove non-acidic compound (mainly
unreacted aryl halide), then the basic water was acidified to pH 3
and extracted three times with ethyl acetate. The combined organ-
ic layers were dried over sodium sulphate, filtered, and solvent was
removed under reduced pressure. The residue was purified by
column chromatography, flushed with nitrogen during elution with
ethyl acetate/methanol (20:1).
1
2-Methyl-1-(4-methylpyridin-2-yl)indoline 10bb: H NMR (200 MHz,
CDCl3, 208C, TMS): d=8.17 (d, J=5.3 Hz, 1H), 7.96 (d, J=8.6 Hz,
1H), 7.12–7.20 (m, 2H), 6.82–6.87 (m, 1H), 6.73 (s, 1H), 6.59 (d, J=
5.3 Hz, 1H), 4.60–4.65 (m, 1H), 3.40 (dd, J=9.2, 15.5 Hz, 1H), 2.67
(dd, J=2.6, 15.5 Hz, 1H), 2.30 (s, 3H), 1.33 ppm(d, J=6.3 Hz, 3H).
13C NMR (50 MHz, CDCl3, 208C, TMS): d=155.0 (s), 147.8 (s), 147.7
(d), 144.0 (s), 130.3 (s), 127.0 (d), 124.8 (d), 120.3 (d), 115.8 (d), 113.6
(d), 109.4 (d), 56.5 (d), 36.4 (t), 21.5 (q), 20.0 ppm(q). Elemental anal-
ysis: calcd (%) for C15H16N2 (224.3): C 80.32, H 7.19, N 12.49; found:
C 79.98, H 7.31, N 12.13.
2-Methyl-1-(4-nitrophenyl)indoline 10be: Orange solid, m.p. 92–
1
938C. H NMR (200 MHz, CDCl3, 208C, TMS): d=8.15–8.23 (m, 2H),
7.15–7.31 (m, 5H), 6.91–6.99 (m, 1H), 4.44–4.59 (m, 1H), 3.40–3.52
(dd, J=8.6, 15.6 Hz, 1H), 2.69 (dd, J=2.7, 15.6 Hz, 1H), 1.37–
1.40 ppm(d, J=6.2 Hz, 3H). 13C NMR (50 MHz, CDCl3, 208C, TMS):
d=149.1 (s), 143.7 (s), 140.1 (s), 131.6 (s), 127.5 (d), 126.1 (d, 2C),
126.0 (d), 122.1 (d), 115.2 (d, 2C), 112.2 (d), 59.9 (d), 37.0 (t),
20.2 ppm(q). MS (ESI) m/z(%): 255.2 (100) [M+H]. elemental analy-
sis: calcd (%) for C15H14N2O2 (254.3): C 70.85, H 5.55, N 11.02;
found: C 70.77, H 5.88, N 11.00.
1-(Pyridin-2-yl)-indoline 10aa:[23] Elemental analysis: calcd (%) for
C13H12N2 (196.1): C 79.56, H 6.16, N 14.27; found: C 78.69, H 6.41, N
13.95.
1-(4-Methylpyridin-2-yl)-indoline 10ab:[24] Elemental analysis: calcd
(%) for C14H14N2 (210.1): C 79.97, H 6.71, N 13.32; found: C 79.88, H
7.01, N 13.15.
1
2-Methyl-1-phenylindoline 10bf:[27] Colorless oil. H NMR (200 MHz,
CDCl3, 208C, TMS): d=7.58–7.63 (m, 2H), 7.24–7.49 (m, 4H), 6.99–
1640
www.chemsuschem.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2011, 4, 1637 – 1642

Solvent-Free, Microwave-Assisted N-Arylation of Indolines
2005, pp. 123–135; b) P. M. Dewick, Medicinal Natural Products. A Bio-
synthetic Approac, 2nd ed.; John Wiley and Sons, New York, 2002; c) L.
Xiang, D. Xing, W. Wang, R. Wang, Y. Ding, L. Du, Phytochemistry 2005,
66, 2595–2601.
7.12 (m, 2H), 6.69–6.80 (m, 1H), 4.30–4.47 (m, 1H), 3.33 (dd, J=8.8,
15.6 Hz, 1H), 2.76 (dd, J=7.5, 15.6 Hz, 1H), 1.33 ppm(d, J=6.2 Hz,
3H). 13C NMR (50 MHz, CDCl3, 208C, TMS): d=148.9 (s), 141.5 (s),
129.7 (s), 129.4 (d, 2C), 128.9 (d), 125.0 (d), 123.1 (d), 122.0 (d, 2C),
118.9 (d), 108.6 (d), 60.2 (d), 37.4 (t), 20.2 ppm(q). MS (ESI) m/z(%):
210.2 (100) [M+H]. Elemental analysis: calcd (%) for C15H15N (209.3):
C 86.08, H 7.22, N 6.69; found: C 86.23, H 7.58, N 6.50.
[4] a) F. R. Goodman, G. B. Weiss, M. E. Hurley, Cardiovasc. Drug Rev. 1985, 3,
57–69; b) S. M. Bromidge, M. Duckworth, I. T. Forbes, P. Ham, F. D. King,
K. M. Thewlis, F. E. Blaney, C. B. Naylor, T. P. Blackburn, G. A. Kennett,
M. D. Wood, S. E. Clarke, J. Med. Chem. 1997, 40, 3494–3496; c) R. J.
Mathvink, A. M. Barritta, M. R. Candelore, M. A. Cascieri, L. Deng, L. Tota,
C. D. Strader, M. J. Wyvratt, M. H. Fisher, A. E. Weber, Bioorg. Med. Chem.
Lett. 1999, 9, 1869–1874; d) H. Sano, T. Noguchi, A. Tanatani, Y. Hashi-
moto, H. Miyachi, Bioorg. Med. Chem. 2005, 13, 3079–3091; e) L. A.
Hobson, W. A. Nugent, S. R. Anderson, S. S. Deshmukh, J. J. Haley, P. Liu,
N. A. Magnus, P. Sheeran, J. P. Sherbine, B. R. P. Stone, J. Zhu, Org. Pro-
cess Res. Dev. 2007, 11, 985–995; f) R. Forsblom, K. Paulsen, D. Rotticci,
E. Santangelo, M. Waldman (Astra Zeneca AB, Sweden), PCT
WO 2010053438, CAN 152:568156, 2010.
(S)-1-(4-Nitrophenyl)indoline-2-carboxylic acid 10ce: Dark orange
solid, m.p. 155–1568C. 1H NMR (200 MHz, CDCl3, 208C, TMS): d=
8.20 (d, J=8.9 Hz, 2H), 7.19–7.41 (m, 5H), 6.97 (dd, J=1.1, 7.3 Hz,
1H), 4.85 (dd J=2.9, 10.6 Hz, 1H), 3.69 (dd J=10.6, 16.1 Hz, 1H),
3.31 ppm(dd J=2.9, 16.1 Hz, 1H). 13C NMR (50 MHz, CDCl3, 208C,
TMS): d=175.9 (s), 148.9 (s), 144.2 (s), 141.0 (s), 129.9 (s), 127.9 (d),
125.9 (2C, d), 125.6 (d), 122.5 (d), 115.7 (2C, d), 111.9 (d), 65.0 (d),
33.8 ppm(t). IR (KBr): n˜ =1671 cmÀ1 MS (ESI-) m/z(%): 283.1 (100)
[M+-H]. Elemental analysis: calcd (%) for C15H12N2O4 (284.3): C
63.38, H 4.25, N 9.85; found: C 63.45, H 4.58, N 9.79. [a]2D0 =À40.4
(c=0.02 in CHCl3).
[5] M. Somei, F. Yamada, Nat. Prod. Rep. 2004, 21, 278–311.
[6] a) T. Mino, K. Wakui, S. Oishi, Y. Hattori, M. Sakamoto, T. Fujita, Tetrahe-
dron: Asymmetry 2008, 19, 2711–2716; b) F. Andersson, E. Hedenstrom,
Tetrahedron: Asymmetry 2006, 17, 1952–1957 and references cited
therein.
[7] a) D. Wechsler, Y. Cui, D. Dean, B. Davis, P. G. Jessop, J. Am. Chem. Soc.
2008, 130, 17195–17203; b) M. J. Casas-Catalꢂn, M. T. Domenech-Carbꢃ,
Anal. Bioanal. Chem. 2005, 382, 259–268.
[8] a) D. Kuang, S. Uchida, R. Humphry-Baker, S. M. Zakeeruddin, M. Graet-
zel, Angew. Chem. 2008, 120, 1949–1953; Angew. Chem. Int. Ed. 2008,
47, 1923–1927; b) H. Tanaka, A. Takeichi, K. Higuchi, T. Motohiro, M.
Takata, N. Hirota, J. Nakajima, T. Toyoda, Sol. Energy Mater. Sol. Cells
2009, 93, 1143–1148; c) M. Matsui, Y. Asamura, Y. Kubota, K. Funabiki, J.
Jin, T. Yoshida, H. Miura, Tetrahedron 2010, 66, 7405–7410; d) Y. Sakura-
gi, X.-F. Wang, H. Miura, M. Matsui, T. Yoshida, J. Photochem. Photobiol. A
2010, 216, 1–7; e) H. Yu, J. Li, D. Wu, Z. Qiu, Y. Zhang, Chem. Soc. Rev.
2010, 39, 464–473.
[9] a) D. Liu, G. Zhao, L. Xiang, Eur. J. Org. Chem. 2010, 3975–3984 and ref-
erences cited therein; b) S. Anas, H. B. Kagan, Tetrahedron: Asymmetry
2009, 20, 2193–2199; c) B. W. Boal, A. W. Schammel, N. K. Garg, Org.
Lett. 2009, 11, 3458–3461; d) R. Kuwano, M. Kashiwabara, K. Sato, T. Ito,
K. Kaneda Y. Ito, Tetrahedron: Asymmetry 2006, 17, 521–525; e) H. Sano,
T. Noguchi, A. Tanatani, Y. Hashimoto, H. Miyachi, Bioorg. Med. Chem.
2005, 13, 3079–3091.
[10] a) C. E. Houlden, C. D. Bailey, J. Gair Ford, M. R. Gagne, G. C. Lloyd-Jones,
K. I. Booker-Milburn, J. Am. Chem. Soc. 2008, 130, 10066–10067; b) K.-T.
Yip, M. Yang, K.-L. Law, N.-Y. Zhu, D. Yang, J. Am. Chem. Soc. 2006, 128,
3130–3130; c) J. E. Ney, M. B. Hay, Q. Yang, J. P. Wolfe, Adv. Synth. Catal.
2005, 347, 1614–1620; d) J.-S. Yang, K.-L. Liau, C.-M. Wang, C.-Y. Hwang,
J. Am. Chem. Soc. 2004, 126, 12325–12335; e) H. J. C. Deboves, C.
Hunter, R. F. W. Jackson, J. Chem. Soc. Perkin Trans. 1 2002, 733–736.
[11] a) J. S. Sawyer, E. A. Schmittling, J. A. Palkowitz, W. J. III Smith, J. Org.
Chem. 1998, 63, 6338–6343; b) Z. Liu, R. C. Larock, J. Org. Chem. 2006,
71, 3198–3209; c) T. Mino, Y. Tanaka, Y. Hattori, T. Yabusaki, H. Saotome,
M. Sakamoto, T. Fujita, J. Org. Chem. 2006, 71, 7346–7353; d) T. Mino, Y.
Tanaka, Y. Hattori, M. Tanaka, M. Sakamoto, T. Fujita, Lett. Org. Chem.
2004, 1, 67–69; e) T. Mino, Y. Tanaka, T. Yabusaki, D. Okumura, M. Saka-
moto, T. Fujita, Tetrahedron: Asymmetry 2003, 14, 2503–2506.
Methyl 1-(4-nitrophenyl)indoline-2-carboxylate 10de: Red sticky
1
solid. H NMR (200 MHz, CDCl3, 208C, TMS): d=8.17–8.22 (m, 2H),
7.18–7.37 (m, 5H), 6.92–6.99 (m, 1H), 4.85 (dd, J=3.5, 10.4 Hz, 1H),
3.76 (s, 3H), 3.64 (dd, J=10.4, 16.1 Hz, 1H), 3.26 ppm(dd J=3.5,
16.1 Hz, 1H). 13C NMR (50 MHz, CDCl3, 208C, TMS): d=165.2 (s),
148.9 (s), 144.3 (s), 133.0 (s), 129.9 (s), 127.9 (d), 125.9 (2C, d), 125.6
(d), 122.4 (d), 115.7 (2C, d), 111.8 (d), 65.3 (d), 52.9 (q), 33.8 ppm(t).
MS (ESI-) m/z(%): 297.1 (100) [M+-H]. Elemental analysis: calcd (%)
for C16H14N2O4 (298.1): C 64.42, H 4.73, N 9.39; found: C 64.54, H
4.84, N 9.12.
1-(2-(1,3-Dioxolan-2-yl)-4-nitrophenyl)-indoline 10ai: Light-yellow
solid, m.p. 128–1308C. 1H NMR (200 MHz, CDCl3, 208C, TMS): d=
8.59 (s, 1H), 8.19 (d, J=8.9 Hz, 1H), 7.47 (d, J=8.9, 1H), 7.23 (d, J=
6.8 Hz, 1H), 7.04–7.11 (m, 1H), 6.81–6.88 (m, 1H), 6.67 (d, J=7.3 Hz,
1H), 6.06 (s, 1H), 3.93–4.24 (m, 6H), 3.18 ppm(t, J=8.4 Hz, 2H).
13C NMR (50 MHz, CDCl3, 208C, TMS): d=151.1 (s), 148.7 (s), 144.4
(s), 134.4 (s), 131.6 (s), 127.5 (d), 125.8 (d), 125.4 (d), 124.8 (d), 123.0
(d), 120.8 (d), 110.5 (d), 99.3 (d), 65.8 (t, 2C), 56.6 (t), 29.3 ppm(t).
MS (ESI) m/z(%): 313.0 (100) [M+H]. Elemental analysis: calcd (%)
for C17H16N2O4 (312.3): C 65.38, H 5.16, N 8.97; found: C 65.47, H
5.22, N 8.86.
Acknowledgements
We acknowledge MIUR for financial support, and are also grate-
ful to the Centro Interuniversitario sulle Reazioni Pericicliche.
Keywords: arylation · homogeneous catalysis · microwave
chemistry · palladium · sustainable chemistry
[12] B. Schlummer, U. Scholz, Adv. Synth. Catal. 2004, 346, 1599–1626.
[13] a) D. B. Damon, R. W. Dugger, R. W. Scott, Int. Patent WO
2002088085A2, 2001; b) D. B. Damon, R. W. Dugger, S. E. Hubbs, J. M.
Scott, R. W. Scott, Org. Process Res. Dev. 2006, 10, 472–480.
[1] a) D. L. Boger, C. W. Boyce, R. M. Garbaccio, J. A. Goldberg, Chem. Rev.
1997, 97, 787–791; b) D. A. Horton, G. T. Bourne, M. L. Smythe, Chem.
Rev. 2003, 103, 893–930; c) T. Sunazuka, T. Hirose, T. Shirahata, Y. Hari-
gaya, M. Hayashi, K. Komiyama, S. O. Mura, A. B. III Smith, J. Am. Chem.
Soc. 2000, 122, 2122–2123.
[2] a) Z. Gan, P. T. Reddy, S. Quevillon, S. Couve-Bonaire, P. Arya, Angew.
Chem. 2005, 117, 1390–1392; Angew. Chem. Int. Ed. 2005, 44, 1366–
1368; b) A. B. Dounay, L. E. Overman, A. D. Wrobleski, J. Am. Chem. Soc.
2005, 127, 10186; c) K. C. Nicolaou, P. B. Rao, J. Hao, M. V. Reddy, G. Ras-
sias, X. Huang, D. Y. Chen, S. A. Snyder, Angew. Chem. 2003, 115, 1795–
1800; Angew. Chem. Int. Ed. 2003, 42, 1753–1758.
[14] a) E. M. Beccalli, G Broggini, G. Paladino, A. Penoni, C. Zoni, J. Org.
Chem. 2004, 69, 5627–5630; b) E. M. Beccalli, G. Broggini, G. Paladino,
C. Zoni, Tetrahedron 2005, 61, 61–68; c) G. Abbiati, E. M. Beccalli, G.
Broggini, G. Paladino, E. Rossi, Synthesis 2005, 2881–2886; d) G. Abbiati,
E. M. Beccalli, G. Broggini, M. Martinelli, G. Paladino, Synlett 2006, 73–
76; e) E. M. Beccalli, G. Broggini, M. Martinelli, G. Paladino, Tetrahedron
2005, 61, 1077–1082; f) E. M. Beccalli, G. Broggini, F. Clerici, S. Galli, C.
Kammerer, M. Rigamonti, S. Sottocornola, Org. Lett. 2009, 11, 1563–
1566; g) L. Basolo, E. M. Beccalli, E. Borsini, G. Broggini, M. Khansaa, M.
Rigamonti, Eur. J. Org. Chem. 2010, 1694–1703; h) E. M. Beccalli, A. Ber-
nasconi, E. Borsini, G. Broggini, M. Rigamonti, G. Zecchi, J. Org. Chem.
2010, 75, 6923–6932; i) E. M. Beccalli, G. Broggini, A. Fasana, M. Riga-
[3] a) F. Gueritte, J. Fahy, Anticancer Agents from Natural Products (Eds.:
G. M. Cragg, D. G. I. Kingston, D. J. Newman), CRC Press, Boca Raton,
ChemSusChem 2011, 4, 1637 – 1642
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemsuschem.org
1641

E. M. Beccalli et al.
monti, J. Organomet. Chem. 2011, 696, 277–295; j) E. Borsini, G. Broggi-
ni, A. Fasana, S. Galli, M. Khansaa, U. Piarulli, M. Rigamonti, Adv. Synth.
Catal. 2011, 353, 985–994.
reaux, J. P. Bazureau, Tetrahedron Lett. 2007, 48, 5785–5789; d) C.
Ronco, L. Jean, H. Outaabout, P.-Y. Renard, Eur. J. Org. Chem. 2011, 302–
310.
[15] B. H. Lipshutz, D. W. Chung, B. Richa, Adv. Synth. Catal. 2009, 351, 1717–
1721.
[21] a) M. Beller, C. Breindl, T. H. Riermeier, M. Eichberger, H. Trauthwein,
Angew. Chem. 1998, 110, 3571–3573; Angew. Chem. Int. Ed. 1998, 37,
3389–3391; b) J. A. Seijas, M. P. Vꢄzquez-Tato, M. Montserrat Martꢅnez,
Synlett 2001, 6, 0875–0877.
[22] a) R. J. Lundgren, A. Sappong-Kumankumah, M. Stradiotto, Chem. Eur. J.
2010, 16, 1983–1991; b) X. Huang, K. W. Anderson, D. Zim, L. Jiang, A.
Klapars, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125, 6653–6655.
[23] N. Chatani, T. Asaumi, S. Yorimitsu, T. Ikeda, F. Kakiuchi, S. Murai, J. Am.
Chem. Soc. 2001, 123, 10935–10941.
[24] N. Chatani, S. Yorimitsu, T. Asaumi, F. Kakiuchi, S. Murai, J. Org. Chem.
2002, 67, 7557–7560.
[25] a) R. Omar-Amrani, R. Schneider, Y. Fort, Synthesis 2004, 2527–2534;
b) K. Tsubaki, K. Takaishi, D. Sue, K. Matsuda, Y. Kanemitsu, T. Kawabata,
J. Org. Chem. 2008, 73, 4279–4282.
[16] a) P. T. Anastas, J. C. Warner, Green Chemistry: Theory and Practice,
Oxford University Press, Oxford, 1998; b) N. Winterton, Green Chem.
2001, 3, G73–G75; c) P. T. Anastas, J. B. Zimmermann, Environ. Sci. Tech-
nol. 2003, 37, 94 A-101 A; d) S. L. Y. Tang, R. L. S. Smith, M. Poliakoff,
Green Chem. 2005, 7, 761–762; e) P. Tundo, A. Perosa, F. Zecchini, Meth-
ods and Reagents For Green Chemistry, John Wiley & Sons, Oxford, 2007.
[17] a) J. O. Metzger, Angew. Chem. 1998, 110, 3145—3148; Angew. Chem.
Int. Ed. 1998, 37, 2975–2978; ; b) R. S. Varma, Green Chem. 1999, 1, 43–
55; c) K. Tanaka, F. Toda, Chem. Rev. 2000, 100, 1025–1074; d) A. L.
Garay, A. Pichon, S. L. James, Chem. Soc. Rev. 2007, 36, 846–855; e) B.
Rodriguez, A. Bruckmann, T. Rantanen, C. Bolm, Adv. Synth. Catal. 2007,
349, 2213–2233; f) K. Tanaka, F. Toda, Solvent-Free Organic Synthesis,
Wiley-VCH, Weinheim, 2009; g) G. Kaupp, CrystEngComm 2009, 11,
388–403.
[26] N. Yanagihara, Jpn. Kokai Tokkyo Koho 1999, 130, 345094.
[27] B. Zhang, C. Ma, X. Wang, Y. Cai, Faming Zhuanli Shenqing 2003, 141,
23549.
[18] M. J. Gronnow, R. J. White, J. H. Clark, D. J. Macquarrie, Org. Process Res.
Dev. 2005, 9, 516–518.
[19] Y. Zhou, J. G. Verkade, Adv. Synth. Catal. 2010, 352, 616–620.
[20] a) M. Melucci, G. Barbarella, G. Sotgiu, J. Org. Chem. 2002, 67, 8877–
8884; b) A. S. Gajare, K. Toyota, M. Yoshifuji, F. Ozawa, J. Org. Chem.
2004, 69, 6504–6506; c) K. Bourahla, A. Derdour, M. Rahmouni, F. Car-
Received: February 24, 2011
Revised: June 16, 2011
Published online on August 31, 2011
1642
www.chemsuschem.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2011, 4, 1637 – 1642